Lung cancer is an increasingly common cause of cancer-related death in the world, and over 90% of deaths from lung cancer can be attributed to metastasis (Yano, S. et al., Int. J. Cancer 67:211–217, 1996). Lung cancer is histologically classified into two groups, small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC), based on different clinical behavior (the rate of tumor growth, the pattern of tumor progression, the sensitivity to chemo- and radiotherapy). In both types, however, multi-organ metastasis is frequently observed at the time of diagnosis. Bone, following the liver and brain, is the third most common organ of metastasis in lung cancer patients. In particular, bone metastasis causes various severe symptoms by inducing pathological fracture, compression of spinal cord, and hypercalcemia, and reduces the quality of life of the patients (Iguchi, H. et al., Cancer Res. 56:4040–4043, 1996). Though palliative radiotherapy is given to reduce the symptoms for patients with bone metastasis, a novel treatment is necessary for these patients to improve their prognosis.
Recently much attention has been paid to develop a bone metastasis model with human cancer cells in order to understand the molecular mechanism and to develop a treatment. When cancer cells were injected through the intracardiac route into immunodeficient mice, melanoma (Arguello, F. et al., Cancer Res. 48:6876–6881, 1988; Nakai, M. et al., Cancer Res. 52:5395–5399, 1988), breast cancer (Hall, D. G. and Stocia, G., J. Bone Miner. Res. 9:221–230, 1994; Sasaki, A. et al., Cancer Res. 55:3551–3557, 1995), prostate cancer (Shevrin, D. H. et al., Prostate 19:149–154, 1991), and lung cancer (Iguchi, H. et al., Cancer Res. 56:4040–4043, 1996) have been reported to produce bone metastasis.
In these models, tumor cells were injected into the left ventricle of the heart and bone metastasis was developed in 75% of recipient mice. However, intracardiac injection of tumor cells does not seem to be technically easy, and is associated to some extent with sudden death of the animal. Therefore, intracardiac injection of tumor cells imposes a substantial burden on animals, causing ethical and economic problems. As a result, a simple method with good reproducibility of screening a novel agent to solve the important problem, that is, inhibition and/or prevention of bone metastasis, has not yet been developed.